Updated European Society of Blood and Marrow Transplantation consensus recommendations for GVHD prophylaxis and management in hematological malignancies after stem-cell transplantation
KEY TAKEAWAY
This article discussed 38 EBMT consensus recommendation* statements for use in the routine management of GVHD in allogeneic SCT in adult patients with hematological malignancies with the following key updates to the 2014 EBMT recommendations.
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Rabbit anti-thymocyte globulin (rATG) is recommended for preventing GVHD in patients undergoing matched unrelated donor (MUD) allogeneic SCT (Category 1†; 100% consensus) |
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Grade 2 acute GVHD (aGVHD) with isolated skin or upper gastrointestinal tract (GIT) manifestations can be treated with lower steroid doses, such as 1 mg/kg per day methylprednisolone or prednisone (Category 1; 100% consensus) |
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As an initial treatment of bronchiolitis obliterans syndrome, the fluticasone montelukast regimen is recommended in combination with systemic steroids; however, prolonged use of azithromycin after resolution of bronchiolitis obliterans syndrome in chronic GVHD (cGVHD) is not recommended because of the possibility of increased risk of relapse (Category 2A‡; 100% consensus) |
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Addition of novel drugs in the available treatment options is recommended for steroid-refractory aGVHD (Category 2A; 100% consensus) and cGVHD (Category 2B§; 95% consensus) |
WHY THIS MATTERS
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KEY HIGHLIGHTS
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EBMT task force developed 38 statements (29: 100% consensus; 9: 95% consensus), to update the 2014 GVHD recommendations related to GVHD prophylaxis, drug management during GVHD prophylaxis, and treatment of aGVHD and cGVHD. |
Prophylaxis of GVHD
| Category of evidence, Consensus (100%) |
Recommendations | |
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Category 1 | Patients undergoing MRD or MUD allogeneic transplant should receive GVHD prophylaxis with a calcineurin inhibitor plus an antimetabolitea |
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Category 1 | Tacrolimus or ciclosporin can be used in the setting of sibling or MUD transplants. The choice should be made based on experience at the center (e.g., ciclosporin is the standard calcineurin inhibitor adopted in most European centres) |
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Category 1 | Methotrexate is the recommended antimetabolite for patients receiving MAC |
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Category 2A | Mycophenolate mofetil can be used instead of methotrexate for patients receiving MAC in case of contraindications to methotrexate or for those patients who need rapid engraftment (e.g., those with aspergillosis) |
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Category 2A | Mycophenolate mofetil is the recommended antimetabolite for patients receiving non-MAC and RIC |
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Category 1 | rATG should is recommended for preventing GVHD in patients undergoing MUD allogeneic SCTb |
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aIn children (<18 years) many centres use calcineurin inhibitor as a single agent; bIn children (<18 years) many centres use rATG in MUD allogeneic SCT. MAC, myeloablative conditioning; MRD, matched related donor; MUD, matched unrelated donor; RIC, reduced intensity conditioning. |
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Drug management during prophylaxis of GVHD
| Category of evidence, Consensus (100%) |
Recommendations | |
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Category 2A | Ciclosporin concentration should be carefully monitored. When using the two daily doses regimen, the target concentration in the first-week post-transplant should be 200–300 μg/L to efficiently prevent aGVHD |
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Category 2A | Ciclosporin concentrations should be monitored with whole blood sampling for 12 h after a dose; sampling from the lines used for ciclosporin infusion should be avoided |
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Category 2A | The standard duration of ciclosporin prophylaxis is 6 months; however, it needs to be adjusted to the risk of relapse, chimerism, and presence or absence of GVHD. If no GVHD is reported, ciclosporin dose is tapered from 4 months until the regimen is stopped. Faster tapering is recommended if the risk of relapse is high and a bone marrow graft is provided, especially if complete chimerism is reported. The dose is not tapered, if there are signs of aGVHD or cGVHD with the exception of mild cutaneous aGVHD. In cases of persistent disease or relapse and no GVHD, ciclosporin dose can be carefully tapereda |
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Category 2A | Methotrexate is given as a bolus intravenous injection. In MAC transplants, initial methotrexate dose is 15 mg/m2 given on the first day after the transplant; however, lower doses of methotrexate have also been reported in RIC transplants. In MAC transplants, two additional doses of 10 mg/m2 are given on day three and six after the transplant, an additional dose at 11 days after transplant can be administered. Lower doses are usually administered in RIC transplants on 3 and 6 days after the transplant |
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Category 2A | On the basis of expert opinion, we recommend leucovorin rescue after prophylactically given methotrexate; however, no definite evidence supports leucovorin rescue for preventing methotrexate toxicity or enhancing methotrexate efficacy |
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Category 2A | The leucovorin regimen is usually started 24 h after each dose of methotrexate; on the first day after the transplant the leucovorin should be three 15 mg doses every 6 h, the dose should then increase to four 15 mg doses every six hr after methotrexate doses 3-, 6-, and 11-days after the transplant; leucovorin should be administered by intravenous injection |
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Category 2A | Mycophenolate mofetil should be administered intravenously or orally in three 10–15 mg/kg daily doses; the dose should be adapted according to toxicity |
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Category 2A | The recommended total dose of rATG ranges from 2.5–5.0 mg/kg in MRD and 4.5–6.0 mg/kg in MUD transplants; higher doses are associated with a higher risk of infectious complications |
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aIn children (<18 years) with allogeneic SCT for non-malignant diseases, a longer duration of calcineurin inhibitor is often applied. MAC, myeloablative conditioning; RIC, reduced intensity conditioning. |
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Treatment of aGVHD¶
| Category of evidence, Consensus (100%) |
Recommendations | |
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Category 1 | Systemic treatment is initiated for grade 2 or higher aGVHD |
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Category 1 | First-line treatment of aGVHD is methylprednisolone with an initial dose of 2 mg/kg per day; prednisone in a dose of 2.0–2.5 mg/kg per day is regarded as equivalent to methylprednisolone 2.0 mg/kg per day dose |
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Category 1 | Grade 2 aGVHD with isolated skin or upper GIT manifestations can be treated with lower steroid doses, such as 1 mg/kg per day methylprednisolone or prednisone |
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Category 1 | No reduction in the prednisolone dose is recommended during the first 7 days after transplant, but parenteral steroids can be stopped, and oral steroids can be used until all signs of aGVHD have disappeared. Tapering of the dose is a slow, response dependent process: In cases of complete response, steroid dose should be gradually reduced to 10% of the initial dose over a period of approximately four weeks. In cases of steroid-resistant GVHD, long-term use of steroids might cause major complications; therefore, second-line therapy is recommended |
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Category 1 | Non-absorbable oral steroids, such as budesonide (9 mg per day) or oral beclomethasone (1.3–2.0 mg four times a day), can be given in addition to systemic corticosteroids as treatment of gastrointestinal aGVHD |
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Category 2A | There is no standard second-line treatment for aGVHD. Current practice is to prescribe one of the following drugs: Alemtuzumab, α1-antitripsin, basiliximab, cellular therapies (eg, mesenchymal cells and regulatory T-cells) daclizumab, extracorporeal photopheresis, faecal microbiota transplantation, JAK inhibitors (eg, ruxulotinib which is FDA approved), mycophenolate mofetil, methotrexate, pentostatin, rATG, sirolimus, or vedolizumab; for second-line treatment of aGVHD, centres should follow their institutional guidelines, and patients should be treated in clinical trials when possible |
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FDA, US Food and Drug administration; JAK, Janus kinase |
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Treatment of cGVHD#
| Category of evidence, Consensus (100%) |
Recommendations | |
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Category 2A | The first-line treatment of newly diagnosed cGVHD is steroids |
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Category 2A | As an initial treatment of bronchiolitis obliterans syndrome, the fluticasone montelukast regimen is recommended in combination with systemic steroids; however, prolonged use of azithromycin after resolution of bronchiolitis obliterans syndrome is not recommended because of the possibility of increased risk of relapse |
*Please refer to the source publication Penack O, et al. for additional details.
The National Comprehensive Cancer Network classification of evidence and consensus was used to define consensus recommendations; †Category 1: High-level evidence (randomized trials or meta-analyses) and 100% consensus; ‡Category 2A: Lower-level evidence (small, randomized trials) and 100% consensus; §Category 2B: Lower-level evidence (small, randomized trials) and 80–100% consensus; ¶aGVHD was defined using the Mount Sinai Acute GvHD International Consortium group criteria; #cGVHD was defined using the National Institutes of Health 2014 criteria
Reference
Penack O, Marchetti M, Ruutu T, Aljurf M, Bacigalupo A, Bonifazi F, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020: e157–e167. doi: 10.1016/S2352-3026(19)30256-X. PMID: 32004485.
